5-Hydroxytryptamine (5-HT) mediates or regulates a wide variety of behaviors including, for example, cognition, emotion, attention, and appetite among others. In addition, substantial data indicates that 5-HT is involved in mediating the effects of psychomotor stimulants, such as cocaine and 3,4-methylenedioxy-methamphetamine (MDMA or “ecstasy”). Evidence shows that serotonergic systems in the brain also regulate dopaminergic reward systems and other factors, including the conditioning effects that environmental factors have in maintaining drug taking behavior.
It is understood that the various physiologic effects of 5-HT are based on its interaction with a number of different 5-HT receptor subtypes which activate different intracellular signaling systems. Seven families of 5-HT receptors have been identified, including the 5-HT2 receptor family in which three subtypes are known (5-HT(2A), 5-HT(2B) and 5-HT(2C) receptors). The 5-HT(2) receptor family of serotonin receptors represent key sites of action of serotonin in the brain, and likely comprise the major molecular targets for drugs used in treating a variety of diseases including schizophrenia, depression, anxiety, eating disorders, obsessive-compulsive disorder, chronic pain conditions, and obesity.
The 5-hydroxytryptamine 2C receptor (5-HT(2C)), a prominent central serotonin receptor subtype, is widely distributed throughout the central nervous system (CNS) and is thought to play a role in regulating a wide variety of behavioral processes such as mood, appetite, and sexual behavior (1-4). The 5-HT(2A) receptor mediates the hallucinogenic activity of drugs, such as lysergic acid diethylamide (LSD), and is a major target for treating schizophrenia, insomnia, and other disorders (5). The 5-HT(2B) receptor mediates the potentially lethal valvulopathic side effects of several compounds used as prescription drugs. (6, 7)
5-HT(2C) agonists have demonstrated efficacy in preclinical models of depression, obesity, addiction, and psychosis (8-10). Therapeutics that target the 5-HT(2C) receptor offers a promising means for the treatment of CNS related disorders. However, because the 5-HT(2C) receptor is homologous to the two other family members (11), it is important that 5-HT(2C) agonists developed for clinical use show little if any activity at these subtypes (12). To date, several 5-HT(2C) agonists have shown efficacy in preclinical animal models (13-15), and are currently undergoing human trials (13). In particular, one of the most advanced 5-HT(2C) receptor agonist is Lorcaserin, which is an orally active, antiobesity medication presently in two Phase III trials (16).
Drugs may interact with more than one 5-HT(2) receptor sub-type resulting in potentially undesired side effects. For example, in addition to monoamine transporters, fenfluramine exhibits 5-HT(2C) receptor agonism in vivo, and that the anorectic functions of fenfluramine are due primarily to this latter activity, at least in laboratory animals. It is also clear that 5-HT(2B) receptor agonism is likely responsible for the undesirable cardiopulmonary actions of fenfluramine and related drugs.
These findings indicate that there is a need in the art for drugs that interact selectively with 5-HT(2) receptor subtypes, and, in particular, selective 5-HT(2C) receptor agonists, which exhibit minimal effect on 5-HT(2A) and 5-HT(2B) receptors. Selective 5-HT(2C) receptor agonists can be useful for treatment obesity and related or associated disorders, including hypertension, hyperlipidemia, diabetes, and cardiovascular disease, and avoid interaction with several related and unrelated receptors associated with significant morbidity and mortality, e.g., valvular heart disease associated with activation of the 5-HT(2B) receptor subtype and hallucinations associated with activation of the 5-HT(2A) receptor subtype.
Selective 5-HT(2C) receptor agonists can be useful in the treatment of depression, anxiety, panic disorder, schizophrenia, OCD, epilepsy, and migraine, in addition to obesity. 5-HT(2C) receptor agonists are further disclosed in WO 2006/065600 as useful for treatment of Alzheimer's Disease, in prevention or treatment of senile plaques, and in the treatment of sexual dysfunction in males and females, including the treatment of erectile dysfunction.
A number of synthetic compounds have been reported that show 5-HT(2C) receptor agonistic activity, including in U.S. Pat. Nos. 6,962,939; 6,777,407; 7,012,089; 6,953,787; and 7,071,185; U.S. Patent Publication Nos. 2005/197380; 2005/020573; 2006/154290; 2005/026925; 2005/0143452; 2002/032199; and 2005/0261347; and published PCT applications WO 2000/035922; WO 2006/065600; WO 2006/077025; and WO 2005/007614, for example.
An important advance in the art would be the discovery of selective 5-HT(2C) receptor agonists that are useful in the treatment of diseases and conditions wherein 5-HT(2C) receptor agonism provides a benefit, such as psychiatric disorders, addictive behaviors, cognition disorders, obesity, movement disorders, and compound addiction, for example. A significant need exists in the art for efficacious compounds, compositions, and methods useful in the treatment of such diseases and conditions, alone or in conjunction with other therapies used to treat these diseases and conditions. The present invention is directed to meeting this need.